The present invention is generally directed to metal chelating conjugates for use as a metallopharmaceutical diagnostic or therapeutic agent.
Metallopharmaceutical diagnostic and therapeutic agents are finding ever-increasing application in biological and medical research, and in diagnostic and therapeutic procedures. Generally, these agents contain a radioisotope or paramagnetic metal which upon introduction to a subject, become localized in a specific organ, tissue or skeletal structure of choice. When the purpose of the procedure is diagnostic, images depicting the in vivo distribution of the radioisotope, paramagnetic or radioopaque metal can be made by various means, including single photon emission, magnetic resonance and x-ray, depending on the metal selected and substitution pattern on the metal complex. The distribution and corresponding relative intensity of the detected radioisotope, paramagnetic or radioopaque metal not only indicates the space occupied by the targeted tissue, but may also indicate a presence of receptors, antigens, aberrations, pathological conditions, and the like. When the purpose of the procedure is therapeutic, the agent typically contains a radioisotope and the radioactive agent delivers a dose of radiation to the local site.
Depending upon the target organ or tissue of interest and the desired diagnostic or therapeutic procedure, a range of metallopharmaceutical agents may be used. One common form is a conjugate comprising a radioactive or paramagnetic metal, a carrier agent for targeting the conjugate to a specific organ or tissue site, and a linkage for chemically linking the metal to the carrier. In such conjugates, the metal is typically associated with the conjugate in the form of a coordination complex, more typically as a chelate of a macrocycle. See, e.g., Liu, U.S. Pat. No. 6,916,460.
In U.S. Pat. No. 6,143,274, Tweedle et al. disclose a method for imaging mammalian tissue utilizing a non-ionic complex of a paramagnetic ion of a lanthanide element and a macrocyclic chelating agent. A non-ionic complex, however, is less stable than an anionic complex (i.e., the anionic complex tends to exhibit stronger electrostatic interaction between the cationic metal and anionic ligand).
Metallopharmaceuticals utilizing metal coordinating moieties having a hydroxybenzyl group to assist in the coordination are well known, e.g., HBED. It has been well-demonstrated that the phenolic oxygen, in concert with an aminomethyl moiety situated in an ortho relationship thereto, presents a good chelate forming group for many metals. The need for creating metal coordinating groups that demonstrate higher affinity for metals remains important, however, to reduce the overall toxicity of these compounds. Martell et al. disclose a general description of relevant chelates and metal-binding moieities, while Cacheris et al. recite the importance of the selectivity of chelates for exogenous versus endogenous metals for controlling toxicity (see, A. Martell and R. Smith, Critical Stability Constants, Volume 1: Amino Acides, Plenum Press (1974) and W. Cacheris et al., The Relationship Between Thermodynamics and the Toxicity of Gadnolinium Complexes, Magnetic Resonance Imaging, 8(4), (1990)).